Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents.

Riether, Carsten; Pabst, Thomas; Höpner, Sabine; Bacher, Ulrike; Hinterbrandner, Magdalena; Banz, Yara; Müller, Rouven; Manz, Markus G.; Gharib, Walid H.; Francisco, David; Bruggmann, Remy; van Rompaey, Luc; Moshir, Mahan; Delahaye, Tim; Gandini, Domenica; Erzeel, Ellen; Hultberg, Anna; Fung, Samson; de Haard, Hans; Leupin, Nicolas; ... (2020). Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nature medicine, 26(9), pp. 1459-1467. Springer Nature 10.1038/s41591-020-0910-8

[img] Text
Targenting.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy
[img] Text
Merged manuscript file.pdf - Accepted Version
Restricted to registered users only until 1 January 2021.
Available under License Publisher holds Copyright.

Download (5MB) | Request a copy

Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (NCT03030612). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10-3. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Riether, Carsten; Pabst Müller, Thomas Niklaus; Höpner, Sabine; Bacher, Vera Ulrike; Hinterbrandner, Magdalena; Banz Wälti, Yara; Gharib, Walid; Ferreira Francisco, David Miguel; Bruggmann, Rémy and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1078-8956

Publisher:

Springer Nature

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

07 Jul 2020 09:00

Last Modified:

12 Sep 2020 01:32

Publisher DOI:

10.1038/s41591-020-0910-8

PubMed ID:

32601337

BORIS DOI:

10.7892/boris.145058

URI:

https://boris.unibe.ch/id/eprint/145058

Actions (login required)

Edit item Edit item
Provide Feedback